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Facilitating End-To-End Development of Individualized Therapeutics Public Workshop U.S Facilitating End-to-End Development of Individualized Therapeutics Public Workshop U.S. Food and Drug Administration Center for Biologics Evaluation and Research (CBER) FDA White Oak Campus 10903 New Hampshire Ave. Bldg. 31 Conference Center Great Room Silver Spring, MD 20993 March 3, 2020 This transcript appears as received from the commercial transcribing service after inclusion of minor corrections to typographical and factual errors recommended by the DFO 2 ATTENDEES Albert B. Seymour, PhD Homology Medicines, Inc. Alison Bateman-House, PhD, MPH, MA NYU Grossman School of Medicine Donald B. Kohn, MD UCLA Guangping Gao, PhD University of Massachusetts Jason J. Gill, PhD Texas A&M University Jill A. Wood Phoenix Nest J. Keith Joung, MD, PhD Massachusetts General Hospital Malachi Griffith, PhD Washington University School of Medicine Philip John (PJ) Brooks, PhD National Institutes of Health Robert T. (Chip) Schooley, MD University of California San Diego Center for Biologics Evaluation and Research Gopa Raychaudhuri, PhD (CBER) Center for Biologics Evaluation and Research Peter Marks, MD, PhD (CBER) Center for Biologics Evaluation and Research Zenobia Taraporewala, PhD (CBER) Center for Biologics Evaluation and Research Roger Plaut, PhD (CBER) Center for Biologics Evaluation and Research Anita Richardson, MAS (CBER) Center for Biologics Evaluation and Research Sandhya Sanduja, PhD (CBER) Center for Biologics Evaluation and Research Zuben Sauna, PhD (CBER) Center for Biologics Evaluation and Research Rebecca Reindel, MD (CBER) Center for Biologics Evaluation and Research Larissa Lapteva, MD (CBER) Center for Biologics Evaluation and Research Zhenzhen Xu, PhD (CBER) www.transcriptionetc.com 3 Center for Biologics Evaluation and Research Celia Witten, PhD, MD (CBER) Center for Biologics Evaluation and Research Capt. Julie Vaillancourt (CBER) Stephen Aldrich MyCancerDB Joe Campbell NIAID Matt Kelly Sarepta Therapeutics Sharon Hesterlee Muscular Dystrophy Association Advanced Regenerative Manufacturing Richard McFarland Institute Karen Walker Genentech Jessica Adomako Genentech Marilyn Howard University of Pennsylvania Center for Biologics Evaluation and Research Carolyn Wilson, PhD (CBER) Lea Witkowsky Innovative Genomics Institute Aron Stein Sangamo Therapeutics Lorraine McLellan Audience Questioner Lynne McGrath Audience Questioner Neil Thakur ALS Association Rich Horgan Cure Rare Disease Anita Nosratieh FasterCures Lauren Black Charles River Laboratories www.transcriptionetc.com 4 TABLE OF CONTENTS INTRODUCTION: DR. GOPA RAYCHAUDHURI .....................................................6 SPEAKER: DR. PETER MARKS .................................................................................11 SESSION 1: MANUFACTURING .................................................................................22 SESSION 1 MODERATOR INTRODUCTION: DR. ZENOBIA TARAPOREWALA .........................................................................................................22 CHALLENGES AND OPPORTUNITIES IN DEVELOPMENT AND MANUFACTURING OF INDIVIDUALIZED THERAPEUTICS WITH AAV VECTOR-BASED GENE THERAPIES - DR. GUANGPING GAO ........................30 DEVELOPMENT OF PHAGE THERAPY: PERSONALIZED MEDICINE AND INDIVIDUALIZED THERAPEUTICS - DR. JASON J. GILL .................................51 PANEL SESSION WITH Q&A .....................................................................................74 [BREAK] ...........................................................................................................................96 SESSION 2: TOOLS FOR SAFETY TESTING AND DEVELOPMENT ................96 SESSION 2 MODERATOR INTRODUCTION: DR. SANDHYA SANDUJA (CBER) ..............................................................................................................................96 PRECLINICAL APPROACHES/CHALLENGES IN DEVELOPMENT OF INDIVIDUALIZED THERAPEUTICS - DR. ALBERT B. SEYMOUR .................104 BIOINFORMATICS TOOLS FOR DEVELOPMENT, ANALYSIS & PRECLININCAL TESTING OF INDIVIDUALIZED THERAPEUTICS - DR. MALACHI GRIFFITH .........................................................................................128 DEFINING OFF-TARGET EFFECTS OF GENE EDITING TECHNOLOGIES - DR. J. KEITH JOUNG ..................................................................................................150 PANEL DISCUSSION WITH Q&A ............................................................................174 SESSION 3: CLINICAL ...............................................................................................200 SESSION 3 MODERATOR INTRODUCTION: DR. REBECCA REINDEL ........201 OPPORTUNITIES AND CHALLENGES IN THE CLINICAL DEVELOPMENT OF BACTERIOPHAGE THERAPEUTICS - DR. ROBERT T. SCHOOLEY.......209 CHALLENGES TO DEVELOPING INDIVIDUALIZED STEM CELL GENE THERAPIES - DR. DONALD B. KOHN ....................................................................230 PANEL SESSION WITH Q&A ...................................................................................253 SESSION 4: PRODUCTS TO PATIENTS .................................................................276 SESSION 4 MODERATOR INTRODUCTION: DR. CELIA WITTEN ................276 THE TRIALS AND TRIBULATIONS OF DRIVING A TREATMENT FOR AN UBER-RARE DISEASE TO THE CLINIC AND BEYOND-A PARENT’S PERSPECTIVE - MS. JILL A. WOOD ......................................................................286 ETHICAL ISSUES IN PRODUCT DEVELOPMENT AND SUSTAINABILITY FOR INDIVIDUALIZED THERAPIES-DR. ALISON BATEMAN-HOUSE ........308 www.transcriptionetc.com 5 BEYOND ‘ONE DISEASE AT A TIME:’ ACCELERATING CLINICAL TRIALS OF GENETIC THERAPIES BY GROUPING RARE DISEASE PATIENTS ACCORDING TO UNDERLYING DISEASE MECHANISM-DR. PHILIP J. BROOKS ........................................................................................................................330 PANEL DISCUSSION WITH Q&A ............................................................................349 WRAP UP AND CLOSING REMARKS: DR. PETER MARKS .............................378 www.transcriptionetc.com 6 1 INTRODUCTION: DR. GOPA RAYCHAUDHURI 2 3 DR. RAYCHAUDHURI: Good morning, everyone, and 4 welcome to the CBER workshop on facilitation and 5 development of individualized therapeutics. My name is 6 Gopa Raychaudhuri. I'm a senior scientist in the 7 Office of the Director at CBER, and I coordinate and 8 oversee CBER's individualized therapeutics program. 9 It is my distinct pleasure to welcome all the 10 stakeholders who are here today, including patients, 11 family members, patient advocacy organizations, 12 healthcare professionals, and individuals from 13 nonprofit organizations, academia, industry, and 14 government. In addition, I would like to thank 15 everyone who's participating in today's proceedings via 16 webcast. We appreciate you taking the time to join and 17 contribute online. 18 Before we begin today's proceedings, I have a 19 few general announcements. First, please silence your 20 cell phones and any mobile devices. If you haven't 21 done so already, we ask that all attendees sign in at www.transcriptionetc.com 7 1 the registration tables just outside this meeting room. 2 If you would like to preorder lunch, you can 3 do so at the food kiosk that's just outside the 4 conference room. Lunch must be preordered by 9:30. If 5 you decide not to preorder, you may purchase snacks, 6 sandwiches, and other food items a la carte at the 7 kiosk. And that's open until 5:00 today. 8 This meeting is being transcribed, and a live 9 webcast is being recorded. There also is an official 10 photographer, as you can see, who will be taking photos 11 during the course of the workshop. For any urgent 12 issues, please speak to the registration staff that are 13 just outside or any FDA staff member with a tag, and we 14 will be able to assist. 15 I'd like to open today's workshop by defining 16 what we mean by individualized therapeutics and why we 17 need to think differently about development, licensure, 18 and access to these products. Out of thousands of 19 rare, hereditary, and acquired diseases, there are 20 hundreds of disorders affecting one or a small group of 21 people each year that could be addressed with www.transcriptionetc.com 8 1 individualized or bespoke therapies. These therapies 2 are based on engineering a product aimed at the 3 specific mechanism underlying a patent's, or a small 4 group of patients', illness. That is the therapeutic 5 product is engineered specifically for a given patient 6 or small group of patients. 7 Examples include gene therapy or gene editing 8 for monogenic diseases, antisense oligonucleotides, or 9 genetically-engineered phages for multidrug-resistant 10 infection. Today's workshop will focus on 11 individualized therapeutic products regulated by CBER, 12 specifically, gene therapies and phage therapies. But 13 we work in close collaboration with our colleagues in 14 CDER, who are very active in this space to facilitate 15 development of antisense oligonucleotide products for 16 patients with rare diseases. 17 This slide shows the traditional regulatory 18 pathway, from discovery to licensure and post-licensure 19 monitoring, for biologics and other medical products 20 regulated by FDA. Individualized therapeutic products 21 present unique challenges because they do not fit the www.transcriptionetc.com 9 1 traditional paradigm for manufacturing and clinical 2 development. This requires that we think outside the 3 box, to establish an evidence-based, clear, and 4 practical pathway for development,
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